12136 Background: Taxane-induced peripheral neuropathy (TIPN) affects up to 70% of patients receiving taxanes and can lead to severe, irreversible symptoms that impair daily functioning and quality of life. Approximately 25% of patients require taxane dose modification or discontinuation to prevent TIPN, compromising treatment effectiveness and survival. Self-reported Black patients experience nearly two times greater incidence of TIPN compared to White patients, contributing to treatment alterations and worse cancer outcomes. Vitamin D insufficiency, which is more common among Black patients, has been implicated as a modifiable risk factor for TIPN. This study assessed the extent to which vitamin D insufficiency mediates the racial disparity in TIPN. Methods: This secondary analysis included self-reported Black or White female patients with early-stage breast cancer treated with paclitaxel-based chemotherapy on the SWOG S0221 phase III trial. The primary endpoint was clinician-assessed grade ≥3 sensory neuropathy per NCI CTCAE attributed to paclitaxel. The mediator was pretreatment vitamin D insufficiency, defined as total 25-hydroxyvitamin D ≤20 ng/mL. Causal mediation analysis decomposed the total effect of race on TIPN into its direct effect and an indirect effect mediated through vitamin D insufficiency, adjusted for age and paclitaxel regimen (weekly or every other week). Log-linear model with modified Poisson regression and weighted logistic regression were used for the outcome model and the mediator model, respectively. Confidence intervals were computed via bootstrapping, and significance was set at α=0.05. Results: A total of 1,106 participants (mean age 51.2 [SD 10] years) were included, of whom 109 were Black and 997 were White. Black patients had a higher prevalence of vitamin D insufficiency (77% vs. 28%, p <0.001) and a higher incidence of grade ≥3 sensory TIPN (29% vs. 14%, p <0.001). The adjusted risk ratio (RR) for TIPN comparing Black to White patients was 2.24 (95% CI, 1.54-3.19; p <0.001). Vitamin D insufficiency statistically mediated this association, with an indirect effect RR of 1.18 (95% CI, 1.01-1.38; p = 0.048), accounting for 27% of the racial disparity in TIPN. The direct effect of race on TIPN, independent of vitamin D status, remained significant (RR 1.90; 95% CI, 1.30-2.85; p <0.001). Conclusions: Vitamin D insufficiency contributes to, but does not entirely explain, the racial disparity in TIPN. While other unaccounted factors may interact with or modify this association, vitamin D supplementation in insufficient patients could partially reduce racial disparities in TIPN and improve pharmacoequity.

Importance:Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective:To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants:This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention:Random assignment to CET or ET. Main Outcomes and Measures:Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results:Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P = .01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P = .003) for postmenopausal participants. Conclusions and Relevance:This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration:ClinicalTrials.gov Identifier: NCT01272037.

BACKGROUND:S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. METHODS:Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. RESULTS:At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). CONCLUSION:As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

BACKGROUND:The RxPONDER trial has guided adjuvant chemotherapy use in node-positive HR+/HER2- breast cancer; however, prior analyses showed poorer outcomes among non-Hispanic Black (NHB) women compared with non-Hispanic White (NHW) women despite similar 21-gene Recurrence Score® (RS) results. This suggests contributors to disparities may not be captured by the composite RS. We evaluated RS gene group components-proliferation, estrogen receptor (ER), HER2 (GRB7), and invasion-by ethnicity, body mass index, and menopausal status, and assessed associations with outcomes. METHODS:RxPONDER enrolled 5,083 women with HR+/HER2- breast cancer, 1-3 positive nodes, and RS ≤ 25, randomized to endocrine therapy ± chemotherapy. 3,102 participants with ethnicity and gene expression data were included. RS components were compared across subgroups, and associations with invasive disease-free survival (IDFS) and distant recurrence-free interval were evaluated using multivariable Cox models adjusted for clinicopathologic factors and treatment. RESULTS:Among 3,102 women (70.2% NHW, 15.5% Hispanic, 9.5% Asian, 4.7% NHB), RS distributions were similar across groups and prognostic overall. Tumors from NHB (p = 0.003) and Hispanic (p = 0.02) had higher proliferation scores versus NHW women, while Asian women had higher HER2 (p = 0.006) and ER scores (p = 0.028). IDFS differences were not statistically significant for NHB vs. NHW women (HR 1.41; 95% CI 0.98-2.03), whereas Asian women had improved IDFS (HR 0.63; 95% CI 0.43-0.91). CONCLUSIONS:Despite similar overall RS distributions, component pathways vary by ethnicity and may contribute to outcome differences. These findings support evaluating gene-specific biology beyond composite scores to better understand disparities and refine risk stratification. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01272037.

QuestionHow does chemoendocrine therapy (CET) compared to endocrine therapy (ET) alone affect cancer-related cognitive impairment (CRCI) in pre- and postmenopausal patients?FindingsThis secondary analysis of the RxPONDER randomized clinical trial included 568 participants assessed at 6, 12, and 36 months and found that CET had a greater negative association with patient-reported cognitive function compared to ET alone in both the pre- and postmenopausal groups.MeaningThese findings indicate that cognitive impairment occurs and persists more frequently with CET than with ET alone among both pre- and postmenopausal patients; therefore, interventions to prevent and treat CRCI are needed. ImportanceBreast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood.ObjectiveTo compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated.Design, Settings, and ParticipantsThis was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025.InterventionRandom assignment to CET or ET.Main Outcomes and MeasuresMean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes.ResultsOf the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P = .01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P = .003) for postmenopausal participants.Conclusions and RelevanceThis secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT01272037 This secondary analysis of the RxPONDER randomized clinical trial assesses patient-reported cognitive impairment by menopausal status among women with breast cancer treated with chemoendocrine therapy vs endocrine therapy alone.

BACKGROUND:The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial. METHODS:The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment. RESULTS:A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity. CONCLUSIONS:NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01272037.

Importance:Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences. Objective:To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment. Design, Setting, and Participants:This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024. Interventions:Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously). Main Outcomes and Measures:The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method. Results:Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable. Conclusions and Relevance:This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone. Trial Registration:ClinicalTrials.gov Identifier: NCT03701334.

Representativeness of Study Participants.

PURPOSE:Prognostic staging after neoadjuvant chemotherapy (NACT) is not included in American Joint Commission on Cancer (AJCC) staging. This study addressed this deficiency by including responses to therapy with standardized staging variables in a validated prognostic staging system for patients treated with NACT. METHODS:The National Cancer Database was queried to identify 140,605 patients treated with NACT between 2010 and 2018. Three response categories (no response, partial response, and complete response [pCR]) were created on the basis of comparison of clinical and post-NACT pathologic staging. Univariate and multivariate analyses of clinical stage, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and grade were analyzed for each category. Predictive models for each response category were validated using the bootstrap technique. Calibration plots compared predicted and observed 3-year survival probabilities in the training and validation data sets. RESULTS:Each validated model demonstrated statistically significant survival differences in the postneoadjuvant prognostic stage assignment. Of all patients with a pCR, 94.2% were assigned to postneoadjuvant ypStage I compared with 35.5% of patients with no response. Advancing clinical stage had a progressive but small impact on overall survival (OS) with pCR (high-grade, triple-negative breast cancer [TNBC]: cStage I, 97% v cStage IIIB/IIIC, 91%; grade 2 luminal A: 97% v 91%) but was associated with a profound decrease in OS with no response for TNBC or HER2+ disease (high-grade TNBC 89% v 50%) and less profound for grade 2 luminal A disease with no response (97% v 81%). CONCLUSION:We present a novel, validated prognostic staging system that predicts OS according to the response to NACT. These data will provide AJCC stage assignments for a growing proportion of patients treated with NACT.

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, and overexpression of all the individual ADAMs tested are correlated with poor patient survival, making it unlikely that targeting a single ADAM member would be effective. Reverse-phase protein array and multiplexed immunofluorescence revealed that ADAM10/15/17 expression was associated with activated mTOR signaling. Individual knockdown of ADAM10, ADAM15, or ADAM17 modestly reduced mTOR signaling, cellular proliferation and survival. However, the concurrent knockdown of the three ADAMs drastically decreased mTOR signaling and cellular aggressiveness. Consistently, combined targeting of ADAMs and mTOR increased inhibitory efficacy compared to monotherapy in ADAM-mTOR-activated tumor growth and invasion in vitro and in immunodeficient and immunocompetent mice. These results establish a functional link between ADAMs and activation of mTOR signaling, suggesting the ADAM-mTOR axis as a therapeutic target and biomarker for ADAM-enriched TNBC and, potentially, other tumor lineages with high ADAM activity.

1012 Background: HRD is observed in up to two-thirds of g BRCA- wildtype TNBC. S1416 (NCT02595905) showed that addition of a PARP inhibitor (veliparib) to cisplatin improved progression-free survival (PFS) in gBRCA -wildtype metastatic TNBC (mTNBC) with HRD phenotype (“ BRCA -like”). In this study, we sought to evaluate concordance between circulating tumor DNA (ctDNA)-based detection of somatic homologous recombination repair (sHRR) alterations and tumor-based HRD and to assess if sHRR deficiency (sHRR+) was associated with benefit from veliparib in g BRCA -wild type mTNBC in SWOG S1416. Methods: S1416 enrolled patients with mTNBC who had received ≤ 1 line of prior therapy and randomized them to cisplatin plus veliparib or placebo. Central gBRCA1/2 testing classified patients as gBRCA -mutated or -wildtype. An a priori defined biomarker panel classified gBRCA -wildtype patients into BRCA -like (HRD+) and non- BRCA -like (HRD-) groups. A third group with gBRCA -wildtype, but without tissue BRCA classification was also included. Pre-treatment and progression plasma samples were utilized for assessment of sHRR status. ctDNA was analyzed using the Guardant OMNI next-generation sequencing platform. sHRR+ was defined by detectable somatic alterations (SNVs, INDELs, fusions with a functional impact notation of deleterious, and/or CNVs with a functional characterization of homozygous deletion) in a 24 gene panel. Results: Among N =213 g BRCA -wildtype patients with evaluable pre-treatment blood samples, 25% were sHRR+. Among sHRR+ patients, alterations in CHEK2 (18%), BRCA1 (17%), BARD1 (8%), ATM (7%), BAP1 (7%), CDK12 (7%), NBN (7%), BRCA2 (5%), and FANCA (5%) accounted for 80% of sHRR alterations. Most sHRR+ patients (91%) had alterations in only one of 24 genes, suggesting mutual exclusivity of homologous recombination pathway alterations in ctDNA. sHRR+ status was numerically higher in BRCA -like compared to non- BRCA -like tumors or unclassified tumors (32% vs. 20% vs. 20%, respectively; P =0.12). Among n =98 patients with availability of evaluable pre-treatment and progression samples, 31% were sHRR+ at baseline and 28% were sHRR+ at progression. Numerically, conversion from sHRR+ to sHRR- was more common than conversion from sHRR- to sHRR+ (30% vs. 9%, respectively). sHRR was not prognostic for PFS (median 4.3 (sHRR+) vs. 4.1 (sHRR-) months, respectively; P =0.30) nor predictive of benefit from veliparib ( P =0.40). Conclusions: One-fourth of gBRCA- wildtype mTNBC patients have ctDNA sHRR alterations, and there is incomplete overlap between tumor- and ctDNA-assessed HRD. ctDNA sHRR alterations were mostly mutually exclusive. Approximately one-third of patients with baseline sHRR+ converted to sHRR- at time of progression while receiving DNA damaging chemotherapy. sHRR was not prognostic and did not predict benefit from veliparib in S1416.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively correlated with PARPi resistance in TNBC patient-derived xenograft models, and in PARPi-resistant TNBC patient tumors. These findings reveal that PARP1 p-Y158 facilitates BRG1-mediated HR to resolve the PARP-DNA complex, and PARP1 p-Y158 may indicate PARPi resistance that can be relieved by combining FGFR inhibitors (FGFRis) with PARPis. In summary, we show that FGFRi restores PARP trapping and PARPi antitumor efficacy in PARPi-resistant breast cancer by decreasing HR through the PARP1 p-Y158/BRG1/MER11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRis with PARPis.

Type of Surgery and Adjuvant Therapy Received.

Molecular Subtypes and Pathological Response.

Background: While the landscape of metastatic breast cancer treatment has evolved over the years with incorporation of targeted agents and antibody drug conjugates, chemotherapy continues to be the mainstay of adjuvant treatment for high-risk early breast cancer. S0221 was a previously reported phase III randomized trial performed by the North American Breast Cancer Intergroup (now known as the National Clinical Trials Network [NCTN]) investigating alternative dosing schedules of chemotherapy for early breast cancer. Methods: S0221 investigated weekly (arms 2 and 4) doxorubicin (A)/cyclophosphamide (C) + granulocyte colony stimulating factor (GCSF; filgrastim or pegfilgrastim) versus (vs.) every 2 weeks (Q2W) (arms 1 and 3) schedule AC, followed by paclitaxel (P) given Q2W or weekly for 12 weeks as post-operative adjuvant therapy in node-positive or high-risk node-negative breast cancer. Weekly AC was given as doxorubicin 24mg/m2 IV once per week and cyclophosphamide 60mg/m2 orally once per day with GCSF. Between December 2003 and November 2010, 2716 patients were randomized in a 2x2 factorial design to: 1) 15 weeks of weekly AC vs. 6 cycles of Q2W AC and 2) P weekly vs. P Q2W with GCSF support and this accounted for arms 1-4. After enrollment of 2716 patients, randomization to the two AC arms was stopped for futility and the trial was modified to study only the P schedules. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of Q2W AC and randomized to P weekly vs. Q2W accounting for arms 5-6. Here, we present updated survival outcomes of four arms on the original protocol and report, for the first time, analysis of 578 patients from two additional arms on the revised protocol. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 12.1 years, among the patients treated in the original protocol, there were no significant differences among the four treatment arms for disease free survival [DFS] (p=0.91) or overall survival [OS] (p=0.34). When stratified by disease subtype, the human epidermal receptor-2 (HER2) positive cohort had the highest 10-year DFS rate (77.7%) compared to HR-positive/HER2-negative (70.6%) or HR-negative/HER2-negative (70.3%) cohorts (p value = 0.0005). The HER2-positive cohort also had a superior 10-year OS rate of 82.3% compared to HR-positive/HER2-negative (78.1%) or HR-negative/HER2-negative (74.9%) cohorts (p=0.0044). Among the 578 patients assigned AC for 4 cycles and randomized to P weekly vs. Q2W P, there were no overall differences in DFS (p=0.32) or OS (p=0.42). There was no difference in 10-year DFS rate between original (71.3%) or revised (74.4%) protocol (HR 0.80; 95% CI 0.75-1.05). Patients were also stratified in terms of sex (23 men enrolled) and race (379 Blacks enrolled). While women have superior DFS and OS compared to men, due to small number of men and wide CI, these data should be interpreted with caution. Black patients had worse DFS and OS (10-year DFS rate of 64.2% vs. 72.8%; 10-year OS rate of 70.4% vs. 79.0%) compared to non-Blacks. In terms of toxicity, cardiac toxicity profile was more favorable in arms 2 and 4 (0.5-0.7%) that used weekly AC compared to the other four arms that incorporated AC Q2W (1.1-3.3%). There was more skin toxicity with weekly AC schedule with 15.7-16.1% events compared to 2.4-4.0% events in the other four arms. There was no difference in infectious risk or changes in metabolic profile but there were more neurological AEs, and more pain with arms that used Q2W paclitaxel compared to weekly paclitaxel. Conclusion: As there were no significant outcome differences in DFS or OS between the studied schedules with extended follow-up in the original cohort or in the additional 578 patients treated on the revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Citation Format: Azka Ali, William E Barlow, Halle CF Moore, Timothy J Hobday, Claudine Isaacs, Muhammad Salim, Jonathan K Cho, Kristine J Rinn, Kathy S Albain, Helen K Chew, Gary V Burton, Timothy D Moore, Gordan Srkalovic, Bradley A McGregor, Lawrence E Flaherty, Danika. Long-Term Follow-up and updated analysis from S0221, Comparing Alternative Dose-Schedules of Adjuvant Anthracycline/Taxane Therapy in High-Risk Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF1-04.

Somatic mutations identified by whole exome sequencing. Oncoplot representing the most common somatic mutations assessed by whole exome sequencing (WES) in tumors obtained from patients (n = 23) at the time of diagnosis. Genes with mutations occurring in five or more patients are shown.

Baseline clinicopathologic characteristics and associations with pathologic response

LBA500 Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented. Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and premenopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy. Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals. Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease. Clinical trial information: NCT03701334 .

Background Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.Methods In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for >= 5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.Results As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P=0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.Conclusions Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.) In patients with stage II or III early breast cancer, the addition of ribociclib to adjuvant hormonal therapy resulted in a significant improvement in 3-year invasive disease-free survival.